Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4
Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4
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DOI：
10.1016/j.trsl.2013.08.003
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发表时间：
2013-12-01
影响因子：
7.8
通讯作者：
Russel, Frans G. M.
中科院分区：
文献类型：
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作者：
El-Sheikh, Azza A. K.;Greupink, Rick;Russel, Frans G. M.
肾近端小管转运蛋白在免疫抑制剂的排泄、药代动力学相互作用和毒性中起关键作用。基底外侧有机阴离子转运蛋白（OAT）和顶端多药耐药相关蛋白（MRP）分别参与这些药物的主动肾小管摄取和尿液外排。我们研究了12种免疫抑制剂与OAT 1和OAT 3介导的细胞（H-3）-甲氨蝶呤（MTX）摄取的相互作用，以及从过表达人MRP 2和MRP 4的人胚肾293细胞分离的膜囊泡中三磷酸腺苷依赖性（H-3）-MTX转运。我们的研究结果表明，在临床相关浓度为10 μ M时，麦考酚酸抑制OAT 1和OAT 3介导的（H-3）-MTX（摄取。阿糖胞苷、长春碱、长春新碱、氢化可的松和米托蒽醌仅抑制OAT 1，而他克莫司、硫唑嘌呤、地塞米松、环孢素和6-巯基嘌呤对这两种转运蛋白均无影响。环磷酰胺刺激OAT 1，但不影响OAT 3。关于顶端外排转运体，麦考酚酸，环磷酰胺，氢化可的松，和他克莫司抑制MRP 2和MRP 4，而米托蒽醌和地塞米松刺激（H-3）-MTX运输这两个转运体。环孢素、长春新碱和长春碱仅抑制MRP 2，而6-巯基嘌呤仅抑制MRP 4转运活性。阿糖胞苷和硫唑嘌呤对两种转运蛋白均无影响。总之，我们全面绘制了各种免疫抑制剂对4种关键肾阴离子转运蛋白抑制作用的差异，并提供了免疫抑制剂药物可以调节OAT 1-、OAT 3-、MRP 2-和MRP 4-介导的MD转运（不同程度）的证据。这些数据提供了一个更好的了解肾脏机制的药物相互作用和肾毒性有关的组合方案与这些化合物在临床上。
Renal proximal tubule transporters can play a key role in excretion, pharmacokinetic interactions, and toxicity of immunosuppressant drugs. Basolateral organic anion transporters (OATs) and apical multidrug resistance-associated proteins (MRPs) contribute to the active tubular uptake and urinary efflux of these drugs, respectively. We studied the interaction of 12 immunosuppressants with OAT1- and OAT3-mediated (H-3)-methotrexate (MTX) uptake in cells, and adenosine triphosphate-dependent (H-3)-MTX transport in membrane vesicles isolated from human embryonic kidney 293 cells overexpressing human MRP2 and MRP4. Our results show that at a clinically relevant concentration of 10 mu M, mycophenolic acid inhibited both OAT1- and OAT3-mediated (H-3)-MTX( uptake. Cytarabine, vinblastine, vincristine, hydrocortisone, and mitoxantrone inhibited only OAT 1, whereas tacrolimus, azathioprine, dexamethasone, cyclosporine, and 6-mercaptopurine had no effect on both transporters. Cyclophosphamide stimulated OAT1, but did not affect OAT3. With regard to the apical efflux transporters, mycophenolic acid, cyclophosphamide, hydrocortisone, and tacrolimus inhibited MRP2 and MRP4, whereas mitoxantrone and dexamethasone stimulated (H-3)-MTX transport by both transporters. Cyclosporine, vincristine, and vin-blastine inhibited MRP2 only, whereas 6-mercaptopurine inhibited MRP4 transport activity only. Cytarabine and azathioprine had no effect on either transporter. In conclusion, we charted comprehensively the differences in inhibitory action of various immunosuppressive agents against the 4 key renal anion transporters, and we provide evidence that immunosuppressant drugs can modulate OAT1-, OAT3-, MRP2-, and MRP4-mediated transport of MD( to different extents. The data provide a better understanding of renal mechanisms underlying drug-drug interactions and nephrotoxicity concerning combination regimens with these compounds in the clinic.